US4622178A - Process for preparing azetidinone derivatives - Google Patents
Process for preparing azetidinone derivatives Download PDFInfo
- Publication number
- US4622178A US4622178A US06/608,695 US60869584A US4622178A US 4622178 A US4622178 A US 4622178A US 60869584 A US60869584 A US 60869584A US 4622178 A US4622178 A US 4622178A
- Authority
- US
- United States
- Prior art keywords
- acid
- sub
- compound
- phenyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title abstract description 10
- -1 phenyloxymethyl group Chemical group 0.000 claims abstract description 80
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- HCXJFMDOHDNDCC-UHFFFAOYSA-N 5-$l^{1}-oxidanyl-3,4-dihydropyrrol-2-one Chemical group O=C1CCC(=O)[N]1 HCXJFMDOHDNDCC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 150000003978 alpha-halocarboxylic acids Chemical class 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- VYGSFTVYZHNGBU-UHFFFAOYSA-N trichloromethanesulfonic acid Chemical compound OS(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- MZGNSEAPZQGJRB-UHFFFAOYSA-N dimethyldithiocarbamic acid Chemical compound CN(C)C(S)=S MZGNSEAPZQGJRB-UHFFFAOYSA-N 0.000 claims 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- KQQUGBMRGJUCHF-UHFFFAOYSA-N CCN(CC)C([SH2]SC(OCC(SC1=NN=NN1)(SC1=NN=NN1C)SC1=NN=NN1C1=CC=CC=C1)=S)=S Chemical compound CCN(CC)C([SH2]SC(OCC(SC1=NN=NN1)(SC1=NN=NN1C)SC1=NN=NN1C1=CC=CC=C1)=S)=S KQQUGBMRGJUCHF-UHFFFAOYSA-N 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229910052717 sulfur Chemical group 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- 150000003536 tetrazoles Chemical class 0.000 claims 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 11
- 125000002252 acyl group Chemical group 0.000 abstract description 5
- 150000007522 mineralic acids Chemical class 0.000 abstract description 5
- 150000007524 organic acids Chemical class 0.000 abstract description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 abstract description 5
- 125000005499 phosphonyl group Chemical group 0.000 abstract description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 5
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 125000004354 sulfur functional group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical group N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 101100177155 Arabidopsis thaliana HAC1 gene Proteins 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910004809 Na2 SO4 Inorganic materials 0.000 description 1
- 101100434170 Oryza sativa subsp. japonica ACR2.1 gene Proteins 0.000 description 1
- 101100434171 Oryza sativa subsp. japonica ACR2.2 gene Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HDFRDWFLWVCOGP-UHFFFAOYSA-N carbonothioic O,S-acid Chemical group OC(S)=O HDFRDWFLWVCOGP-UHFFFAOYSA-N 0.000 description 1
- 125000006243 carbonyl protecting group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229950004394 ditiocarb Drugs 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000001701 trimethoxybenzyl group Chemical group 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the ratio between the compound (II) and the compound (III) is not particularly limited and accordingly can be suitably determined over a wide range.
- the latter is used in an amount of usually about 1 to about 10 moles, preferably about 1 to 2 moles, per mole of the former.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing an azetidinone derivative represented by the formula ##STR1## wherein R1 represents a straight-chain or branched-chain lower alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted phenylmethyl group or substituted or unsubstituted phenyloxymethyl group, R2 represents hydrogen atom, an optionally substituted hydrocarbon residue or protective group for amino group selected from the class consisting of acyl, silyl, sulfonyl and phosphonyl derived from organic or inorganic acid, and R3 represents a substituted or unsubstituted aryl group or the residue of substituted or unsubstituted heterocyclic ring.
Description
This invention relates to a process for preparing azetidinone derivatives and more particularly to a process for preparing azetidinone derivatives represented by the formula ##STR2## wherein R1 represents a straight-chain or branched-chain lower alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted phenylmethyl group or substituted or unsubstituted phenyloxymethyl group, R2 represents hydrogen atom, an optionally substituted hydrocarbon residue or protective group for amino group selected from the class consisting of acyl, silyl, sulfonyl and phosphonyl derived from organic or inorganic acid, and R3 represents a substituted or unsubstituted aryl group or the residue of substituted or unsubstituted heterocyclic ring.
The azetidinone derivatives of the formula (I) are important compounds as intermediates for synthesizing cephalosporin-type antibiotics.
Conventional processes for preparing the azetidinone derivatives of the formula (I) include those which involve the reaction between thiol and sulfenic acid formed by thermal decomposition of penicillin sulfoxide, for example, the reaction of penicillin G-S-oxide with 2-mercaptobenzothiazole [T. Kamizya et al., Tetrahedron Lett., 3001 (1973)]. With this process, however, the amino-protecting group R2 of the compound (I) is restricted by the substituents of the penicillin which is one of the reactants. Processes are known for synthesizing the compounds (I) having various amino-protecting groups R2 for amino which processes comprise reacting a thiazolinoazetidinone derivative having the corresponding amino-protecting groups R2 with a sulphenyl halide in a hydrous organic solvent [S. Torii et al., Tetrahedron Lett., 2495 (1982)]. However, this process involves the preparation of a sulfenyl halide by reacting the corresponding disulfide or thiol with a halogen such as chlorine or bromine and thus entails complicated reaction operation. Further the process requires an excess amount of a sulfenyl halide because of its decomposition in a hydrous solution and involves a cumbersome treatment for separating the decomposed sulfenyl halide. For these reasons, the process poses problems in terms of commercial mass production.
We have conducted extensive research to develop a process using disulfide serving as an agent for converting the starting material to sulfenyl without employing halogen and found that the contemplated compound can be prepared by a simple procedure of reacting a compound having the skeleton of 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene with an acid in a hydrous organic solvent in the presence of dibenzothiazolyldisulfide. The invention has been accomplished based on this novel finding.
This invention provides a process for preparing an azetidinone derivative represented by the formula ##STR3## wherein R1 represents a straight-chain or branched-chain lower alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted phenylmethyl group or substituted or unsubstituted phenyloxymethyl group, R2 represents hydrogen atom, an optionally substituted hydrocarbon residue or amino-protecting group selected from the class consisting of acyl, silyl, sulfonyl and phosphonyl derived from inorganic or organic acid, and R3 represents a substituted or unsubstituted aryl group or the residue of substituted or unsubstituted heterocyclic ring, the process comprising reacting a thiazolinoazetidinone derivative represented by the formula ##STR4## wherein R1 and R2 are as defined above with a sulphur-containing compound represented by the formula
R.sup.3 --S--Y (III)
wherein R3 is as defined above and Y represents --SR3 or ##STR5## (in which R3 is as defined above and R4 and R5 each represent a cyclic or acyclic amine residue or imido residue) in the presence of an acid in a hydrous organic solvent.
The process of this invention eliminates the need to use a sulfenyl halide which requires special care in handling and gives the contemplated compound in a high yield by carrying out a simple procedure under mild conditions. This process facilitates the separation and purification of the contemplated compound (I) and is significantly advantageous in feasibility of commercial mass production.
The starting compounds of the formula (II) to be used in the reaction of this invention can be any of the compounds having the skeleton of 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene and possessing substituents which do not undergo undesired change when reacted under the conditions of this invention. Examples of the groups represented by R1 are methyl, ethyl, isopropyl, butyl, pentyl, hexyl and like straight-chain or branched-chain lower alkyl groups; phenyl, p-nitrophenyl, p-chlorophenyl and like substituted or unsubstituted aryl groups; benzyl, p-nitrophenylmethyl, p-chlorophenylmethyl, p-methoxyphenylmethyl, diphenylmethyl and like substituted or unsubstituted phenylmethyl groups; phenoxymethyl, p-nitrophenoxymethyl, p-chlorophenoxymethyl and like substituted or unsubstituted phenyloxymethyl groups; etc.
The atom represented by R2 is hydrogen and examples of the groups R2 are amino-protecting groups such as acyl, silyl, sulfonyl and phosphonyl derived from inorganic or organic acid and optionally substituted hydrocarbons, etc. Examples of acyl, silyl, sulfonyl, phosphonyl and like amino-protecting groups derived from inorganic or organic acid are acetyl, propionyl, butyryl, trimethylsilyl, dimethylbutylsilyl, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, diphenylphosphonyl, dibenzylphosphonyl, diethylphosphonyl, etc. Exemplary of the substituted hydrocarbons are those of the formulae ##STR6##
In the formulae (IV) to (VII), R is hydrogen atom or carboxyl-protecting group, Z1 and Z2 are the same or different and are each hydrogen atom, halogen atom, sulphur group, oxygen group, nitrogen group or the like and W is a protected hydroxyl group. Representative of the carboxyl-protecting groups represented by R are benzyl, p-methoxybenzyl, trimethoxybenzyl, trimethoxydichlorobenzyl, piperonyl, diphenylmethyl, bis(p-methoxyphenyl)methyl, ditolylmethyl, phenyl-p-methoxyphenylmethyl, α-p-methoxyphenylethyl, α-p-methoxyphenyl-β-trichloroethyl, trichloroethyl, florenyl, tert-butyl, trityl, α-diphenylethyl, cumyl, p-nitrobenzyl, o-nitrobenzyl, o,p-dinitrobenzyl, phenacyl, p-bromophenacyl, 1-methoxycarbonyl-2-oxopropyl, methoxyethoxymethyl, methoxymethyl, benzyloxymethyl, isopropoxymethyl, etc. Examples of the substituents represented by Z1 and Z2 are bromine, chlorine, fluorine and like halogen atoms; methylthio, ethylthio, phenylthio, p-nitrophenylthio, pentachlorophenylthio, 2-pyridylthio, 2-benzothiadiazolylthio, 1,3,4-thiadiazole-5-ythio, 2-substituted-1,3,4-thiadiazole-5-ylthio, 1,2,3,4-tetrazole-5-ylthio, 1-substituted-1,2,3,4-tetrazole-5-ylthio, o-ethyldithiocarbonate, N,N-diethyldithiocarbamate, phenylsulfonyl, p-methylphenylsulfonyl and like sulphur groups; hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, nitrosoxy, nitryloxy, and like oxygen groups, dimethylamino, piperidine-1-yl and like nitrogen groups; etc. Examples of the protected hydroxyl groups represented by W are diphenylphosphonyloxy, methanesulfonate, N-morphonyl, diphenylmethyloxy, etc.
The starting material (II) can be prepared by reacting the corresponding ester of penicillin-1-oxide of the formula (VIII) with more than an equivalent of trimethylphosphorous acid with refluxing in benzene as a solvent, as shown below in a reaction equation or by further treating the reaction product resulting from the foregoing procedure according to a conventional method [S. Torii et al., Tetrahedron Lett., 3198 (1981)]. ##STR7##
Illustrative of the sulphur-containing compounds of the formula R3 --S--Y (wherein R3 and Y are as defined above) which are used in the reaction of the invention are a disulfide wherein Y is --S--R3, sulfenamido wherein Y is ##STR8## and sulfenimido. Representative of the groups R3 are phenyl, p-nitrophenyl, pentachlorophenyl and like substituted or unsubstituted aryl groups; 2-pyridyl, 2-benzothiazolyl, 1,3,4-thiadiazole-5-yl, 2-methyl-1,3,4-thiadiazole-5-yl, 1,2,3,4-tetrazole-5-yl, 1-methyl-1,2,3,4-tetrazole-5-yl, 1-phenyl-1,2,3,4-tetrazole-5-yl, benzimidazole and like substituted or unsubstituted heterocyclic rings; etc. Examples of the groups ##STR9## are diethylamine, diisopropylamine and like primary or secondary amine residues; cyclohexylamine, morpholine, piperidine, pyrrolidine, and like cyclic amine residues; phthalimido, succinimido and like imido residues; etc.
The ratio between the compound (II) and the compound (III) is not particularly limited and accordingly can be suitably determined over a wide range. The latter is used in an amount of usually about 1 to about 10 moles, preferably about 1 to 2 moles, per mole of the former.
The reaction of this invention is conducted in a hydrous organic solvent in the presence of an acid. The water content in the hydrous organic solvent is not particularly restricted but is usually 1 to 1000 equivalents, preferably about 10 to about 500 equivalents, relative to the compound (II). Suitable organic solvents include, for example, pentane, hexane, benzene, toluene and like hydrocarbons; methylene chloride, chloroform, carbon tetrachloride, dichlorobenzene and like halogenated hydrocarbons; methyl formate, methyl acetate, ethyl acetate, butyl acetate and like esters; diethyl ether, dimethyl ether, tetrahydrofuran, dioxane and like ethers; methanol, ethanol, butanol, ethylene glycol and like alcohols; formic acid, acetic acid, propionic acid and like carboxylic acids; acetonitrile, benzonitrile and like nitriles; dimethylformamide, dimethylacetamide and like amides; dimethylsulfoxide and like sulfoxides; nitromethane, nitroethane and like nitrohydrocarbons; acetone, cyclohexane and like ketones; etc. These solvents are used singly or in mixture. Preferred examples of useful organic solvents are ethers, ketones, alcohols, amides, sulfoxides and like hydrophilic polar solvents or a mixture of other class of solvent and such hydrophilic solvent. The amount of the solvent, although variable with the selection of the compounds (II) and (III), is usually 1 to 1000 parts, preferably 2 to 500 parts, per part of the compound (II).
Examples of useful acids are hydrogen halogenide, sulphuric acid, nitric acid, phosphoric acid, perchloric acid, chloric acid and like mineral acids; alkanesulfonic acid, arylsulfonic acid, aralkylsulfonic acid, α-haloalkanesulfonic acid and like sulfonic acids; α-halocarboxylic acid, polycarboxylic acid and like carboxylic acids; etc. among which those having a dissociation constant of about over 0.01 are preferred. Representative of such preferred acids are perchloric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, hydrofluoric acid, nitric acid, phosphoric acid, benzenesulfonic acid, toluenesulfonic acid, etc. The amount of the acid, although variable with the selection of the compounds (II) and (III) and the solvent, reaction temperature and other conditions, is usually about 0.01 to about 50 moles, preferably about 0.1 to about 10 moles, per mole of the substrate.
When a side reaction is caused by the decomposition of an azetidinone ring and an amino-protecting group R2 and the like, the contemplated compound can be produced in high yields by appropriately determining the class and concentration of the acid, reaction temperature, reaction time and like conditions. The reaction of this invention rapidly proceeds at a temperature usually about 0° to about 50° C., preferably about 15° to about 35° C., and is completed usually in about 5 minutes to 1 hour, whereby the contemplated compound can be produced in high yields.
The contemplated compound thus obtained is extracted and isolated in the usual manner after completion of the reaction, and can be easily purified by conventional methods such as precipitation, filteration, recrystallization, chromatography or the like.
Of the present compounds of the formula (I), those wherein R1 is a straight-chain or branched-chain lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenylmethyl, or substituted or unsubstituted phenyloxymethyl, R2 is ##STR10## (in which R is hydrogen or carbonyl-protecting group) and R3 is substituted or unsubstituted aryl or the residue of substituted or unsubstituted heterocyclic ring are novel compounds undisclosed in literature.
The azetidinone derivatives prepared by the process of this invention can be each made into a cephalosporin-type antibiotic of the formula (IX) or (X), as indicated below in Reaction Equation-1 and Reaction Equation-2 (cf. Reference Example to be described later). ##STR11##
In Reaction Equation-1, R1 R3 and R are as defined above and R6 is a substituted or unsubstituted aryl, the residue of substituted or unsubstituted aromatic heterocyclic ring residue, thiocarboxylic acid residue, thiocarbonic acid residue or thioamido residue. ##STR12##
In Reaction Equation-2, R1, R and R3 are as defined above.
Given below are Examples and Reference Example for clarification of the invention.
Dispersed in 3 ml of tetrahydrofuran were 54.7 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenate and 72.0 mg of dibenzothiazolyldisulfide. To the dispersion was added 0.75 ml of a 5% aqueous solution of hydrochloric acid and the mixture was stirred at room temperature for 40 minutes. A 10 ml quantity of ethyl acetate was added to the reaction mixture and the insolubles were removed by a glass filter. The filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give 133.3 mg of the residue, which was separated and purified by silica gel column chromatography, affording 84.8 mg of methyl 2-(4-(2-benzothiazolyl)dithio-3-phenylacetamide-2-oxoazetidine-1-yl)-3-methyl-2-butenate as white powder in about 100% yield.
IR (CHCl3): 3400, 1770, 1720, 1672 cm-1.
NMR (CDCl3): δ(ppm) 2.07 (s, 3H), 2.12 (s, 3H), 3.57 (s, 3H), 3.66 (s, 2H), 5.04 (dd, 1H, 5 Hz, 8 Hz), 5.38 (d, 1H, 5 Hz), 6.66 (d, 1H, 8 Hz), 7.28 (s, 5H), 7.20-7.90 (m, 4H).
Thiazolinoazetidinone (II) and disulfide (III) were dispersed in tetrahydrofuran and an acid was added to the dispersion. The mixture was stirred at room temperature for a predetermined period of time. The reaction was conducted under the same conditions as Example 1 except those as shown in Table 1 below, followed by the same post-treatment, whereby the contemplated azetidinone derivative (I) was produced.
Table 1 below shows the reaction conditions and yields and Table 2 below indicates IR and 1 HNMR data.
TABLE 1
__________________________________________________________________________
Compound (II) Compound (III) Reaction
(I)
Example
R.sup.1
R.sup.2 R.sup.3 (III/II)*
Acid time (min.)
Yield
__________________________________________________________________________
(%)
2 PhCH.sub.2
##STR15## Br (1.24)
5% HCl 40 85
3 PhCH.sub.2
##STR16## BT (1.10)
10% HClO.sub.4
40 90
4 PhCH.sub.2
##STR17## BT (1.26)
1N H.sub.2 SO.sub.4
40 65
5 PhCH.sub.2
##STR18## 2-Py (1.45)
5% HCl 40 75
6 PhCH.sub.2
##STR19## 2-Py (1.26)
5% HCl 40 85
7 PhCH.sub.2
##STR20## C.sub.5 Cl.sub.5
(1.20)
5% HCl 40 65
8 PhCH.sub.2
##STR21## BI (1.37)
5% HCl 40 55
9 PhCH.sub.2
##STR22## BT (1.36)
27% p-TsOH
40 98
10 PhCH.sub.2
##STR23## BT (1.08)
13% TFA 40 60
11 PhOCH.sub.2
##STR24## BT (1.40)
5% HCl 40 81
12 PhCH.sub.2
##STR25## BT (1.40)
5% HCl 35 99
13 PhCH.sub.2
##STR26##
##STR27## (1.32)
5% HCl 35 99
14 PhCH.sub.2
##STR28## BT (1.06) 5% HCl
20 85
15 PhCH.sub.2
##STR29## BT (1.30)
5% HCl 40 90
16 PhCH.sub.2
##STR30## BT (1.30)
5% HCl 40 93
17 PhCH.sub.2
##STR31## BT (1.30)
5% HCl 40 92
18 PhCH.sub.2
##STR32## BT (1.30)
5% HCl 40 89
19 PhCH.sub.2
##STR33## BT (1.30)
5% HCl 40 88
20 PhCH.sub.2
##STR34## BT (1.32)
5% HCl 40 75
21 PhCH.sub.2
##STR35## BT (1.50)
5% HCl 40 80
22 PhCH.sub.2
##STR36## BT (1.10)
5% HCl 40 100
23 PhCH.sub.2
H BT (1.06)
5% HCl 36 90
24 PhCH.sub.2
##STR37## BT (1.06)
5% HCl 40 85
__________________________________________________________________________
Note:
##STR38##
##STR39##
TFA, trifluoroacetic acid; Et, ethyl.
*The mole of the compound (III) based on the mole of the compound (II)
(mole/mole).
TABLE 2
__________________________________________________________________________
Compound (I)
R.sup.1
R.sup.2 R.sup.3
__________________________________________________________________________
PhCH.sub.2
##STR40##
##STR41## IR (CHCl.sub.3) 3395, 1775, 1740,
1680 cm.sup.-1 NMR (CDCl.sub.3,
δ) 1.90 (s, 3H), 3.65 (s,
2H), 4.95 (s, 1H), 5.01 (s, 1H),
5.15(bs, 3H), 5.32 (dd, 1H), 4.5Hz,
8Hz), 5.53 (d, 1H, 4.5Hz), 6.46 (d,
1H, 8Hz), 7.28 (s, 5H), 7.30 (s,
5H), 7.20-8.00 (m, 4H)
PhCH.sub.2
##STR42##
##STR43## IR (CHCl.sub.3) 3400, 1770, 1735,
1670 cm.sup.-1 NMR (CDCl.sub.3,
δ) 1.88 (s, 3H), 3.63 (s,
2H), 4.87 (s, 1H), 4.99 (s, 1H),
5.12 (bs, 2H), 5.10-5.30 (m, 1H),
5.32 (s, 1H), 5.54 (d, 1H, 5Hz),
7.00-7.70 (m, 13H), 8.35 (m, 2H)
PhCH.sub.2
##STR44##
##STR45## IR (CHCl.sub.3) 3390, 1770, 1720,
1678 cm.sup.-1 NMR (CDCl.sub.3,
δ) 1.98 (s, 3H), 2.15 (s,
3H), 3.58 (s, 3H), 3.65 (s, 2H),
5.22 (dd, 1H, 5Hz, 8Hz), 5.43 (d,
1H, 5Hz), 6.92 (d, 1H, 8Hz),
7.00-7.80 (m, 7H), 8.30-8.50 (m,
2H)
PhCH.sub.2
##STR46##
##STR47## IR (CHCl.sub.3) 3400, 1770, 1727,
1680 cm.sup.-1 NMR (CDCl.sub.3,
δ) 1.95 (s, 3H), 2.06 (s,
3H), 3.59 (s, 2H), 3.70 (s, 3H),
5.02 (dd, 1H, 5Hz, 8Hz), 5.53 (d,
1H, 5Hz), 6.38 (d, 1H, 8Hz), 7.26
(s, 5H)
PhCH.sub.2
##STR48##
##STR49## IR (CHCl.sub.3) 3380, 3280, 1770,
1720, 1670 cm.sup.-1 NMR
(CDCl.sub.3, δ) 1.97 (s, 3H),
2.20 (s, 3H), 3.58 (s, 3H), 3.72
(s, 2H), 4.76 (dd, 1H, 5Hz, 8Hz),
4.96 (d, 1H, 5Hz), 6.75 (d, 1H,
8Hz), 7.00-7.50 (m, 10H)
PhOCH.sub.2
##STR50##
##STR51## IR (neat) 3320, 1775, 1735, 1675
cm.sup.-1 NMR (CDCl.sub.3, δ)
4.30 (s, 2H), 4.56 (s, 2H), 5.21
(s, 2H), 5.20-5.70 (m, 5H),
6.70-8.00 (m, 15H)
PhCH.sub.2
##STR52##
##STR53## IR (neat) 3280, 1775, 1740, 1665
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.62 (s, 3H), 3.60 (s, 2H), 4.21
(s, 2H), 5.16 (s, 2H), 5.05-5.40
(m, 3H), 5.46 (s, 1H), 5.55 (d, 1H,
4.5Hz), 7.05 (d, 1H, 8Hz), 7.25 (s,
5H), 7.30 (s, 5H)
PhCH.sub.2
##STR54##
##STR55## IR (neat) 3280, 1775, 1740, 1665
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.66 (s, 2H), 4.15 and 4.89 (ABq,
2H, 11Hz), 5.14 (s, 2H), 5.00-5.40
(m, 3H), 5.50 (s, 1H), 5.55 (d, 1H,
4Hz), 6.92 (d, 1H, 8Hz), 7.10-7.60
(m, 12H), 7.60-8.00 (m, 2H)
PhCH.sub.2
##STR56##
##STR57## IR (neat) 3280, 1780, 1745, 1670,
1235 cm.sup.-1 NMR (CDCl.sub.3,
δ) 2.00 (s, 3H), 3.64 (s,
2H), 4.70 (s, 2H), 5.11 (bs, 3H),
5.18 (dd, 1H, 5Hz, 8Hz), 5.25 (s,
1H), 5.46 (s, 1H), 5.48 (d, 1H,
5Hz), 6.63 (d, 1H, 8Hz), 7.10-7.60
(m, 12H), 7.60-8.00 (m, 2H)
PhCH.sub.2
##STR58##
##STR59## IR (neat) 3280, 1780, 1740, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
1.33 (t, 3H, 7Hz), 3.64 (s, 2H),
4.01 (s, 2H), 4.56 (q, 2H, 7Hz),
5.12 (s, 2H), 5.17 (s, 2H), 5.28
(dd, 1H, 4.5Hz, 8Hz), 5.46 (s, 1H),
5.50 (d, 1H, 4.5Hz), 6.76 (d, 1H,
8Hz), 7.10-7.60 (m, 12H), 7.60-8.00
(m, 2H)
PhCH.sub.2
##STR60##
##STR61## IR (neat) 3300, 1780, 1745, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.31 (bs, 3H), 3.39 (bs, 3H), 3.65
(s, 2H), 4.20 and 4.55 (ABq, 2H,
15Hz), 5.13 (s, 3H), 5.25 (s, 1H),
5.29 (dd, 1H, 4.5Hz, 8Hz), 5.50 (s,
1H), 5.52 (d, 1H, 4.5Hz), 6.76 (d,
1H, 8Hz), 7.20-7.60 (m, 12H),
7.60-8.00 (m, 2H)
PhCH.sub.2
##STR62##
##STR63## IR (neat) 3270, 1780, 1740, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.63 (s, 3H), 3.70 (s, 2H), 4.19
and 4.26 (ABq, 2H, 15Hz), 5.14 (s,
2H), 5.19 (s, 1H), 5.30-5.70 (m,
4H), 7.10-7.50 (m, 13H), 7.60-8.00
(m, 2H)
PhCH.sub.2
##STR64##
##STR65## IR (neat) 3280, 1780, 1740, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.68 (s, 2H), 4.30 (s, 2H), 5.07
(s, 2H), 5.17 (s, 1H), 5.26 (dd,
1H, 4.5Hz, 8Hz), 5.31 (s, 1H), 5.55
(d, 1H, 4.5Hz), 5.59 (s, 1H), 6.83
(d, 1H, 8Hz), 7.10-7.60 (m, 17H),
7.60-8.00 (m, 2H)
PhCH.sub.2
##STR66##
##STR67## IR (neat) 3280, 1780, 1740, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.69 (s, 2H), 3.74 (s, 3H), 4.19
(bs, 2H), 5.10 (bs, 3H), 5.23 (dd,
1H, 4.5Hz, 8Hz), 5.36 (s, 1H), 5.48
(s, 1H), 5.57 (d, 1H, 4.5Hz), 6.79
(d, 1H, 8Hz), 7.10-7.60 (m, 12H),
7.60-8.00 (m, 2H)
PhCH.sub.2
##STR68##
##STR69## IR (CHCl.sub.3) 3390, 1785, 1720,
1670 cm.sup.-1 NMR (CDCl.sub.3,
δ) 3.68 (s, 2H), 4.68 (bs,
2H), 4.73 (bs, 2H), 4.84 (dd, 1H,
5Hz, 7Hz), 4.92 and 5.10 (ABq, 2H,
11Hz), 5.44 (d, 1H, 5Hz), 6.53 (d,
1H, 7Hz), 7.17 (s, 5H), 7.30 (s,
5H), 7.10-7.90 (m, 4H)
PhCH.sub.2
##STR70##
##STR71## IR (CHCl.sub.3) 3395, 1783, 1742,
1672 cm.sup.-1 NMR (CDCl.sub.3,
δ) 3.68 (s, 2H), 4.18 and
4.34 (ABq, 2H, 13Hz), 4.25 (bs,
2H), 4.99 (dd, 1H, 5Hz, 7.5Hz),
5.17 (s, 2H), 5.31 (s, 1H), 5.62
(d, 1H, 5Hz), 6.28 (d, 1H, 7.5Hz),
7.24 (bs, 5H), 7.30 (s, 5H),
7.20-8.00 (m, 4H)
PhCH.sub.2
##STR72##
##STR73## IR (CHCl.sub.3) 3390, 3280, 1770,
1732, 1675 cm.sup.-1 NMR (CD.sub.3
COCD.sub.3, δ) 1.98 (s, 3H),
3.71 (s, 2H), 4.93 (s, 1H), 5.18
(bs, 2H), 5.32 (dd, 1H, 5Hz, 8Hz),
5.58 (d, 1H, 5Hz), 7.30 (s, 5H),
7.10-7.55 (m, 4H), 7.70-8.00 (m,
2H)
PhCH.sub.2
H
##STR74## IR (nujol) 3280, 1790, 1670
cm.sup.-1 NMR (CD.sub.3 SOCD.sub.3,
δ) 3.58 (bs, 2H), 5.20-5.30
(m, 2H), 7.23 (s, 5H), 7.00-7.60
(m, 2H), 7.60-8.00 (m, 2H), 9.10
(m, 2H)
PhCH.sub.2
##STR75##
##STR76## IR (neat) 3280, 1770, 1735, 1665
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.70 (bs, 1H), 3.60 (s, 2H), 4.26
(s, 2H), 5.10 (s, 2H), 5.05-5.40
(m, 3H), 5.49 (d, 1H, 4Hz), 6.84
(d, 1H, 8Hz), 7.10-7.60 (m, 12H),
7.60-7.95 (m, 2H)
__________________________________________________________________________
##STR77##
Dispersed in 2 ml of tetrahydrofuran were 42.2 mg of methyl 2-(3-phenyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenate and 50.2 mg of dibenzothiazolyldisulfide. To the dispersion was added 0.5 ml of a 5% aqueous solution of hydrochloric acid and the mixture was stirred at room temperature for 40 hours. After completion of the reaction, the same subsequent procedure as in Example 1 followed, giving 53.7 mg of methyl 2-(4-(2-benzothiazolyl)dithio-3-benzamido-2-oxo-azetidine-1-yl)-3-methyl-2-butenate in 80% yield.
IR (CHCl3): 3410, 1772, 1722, 1664 cm-1.
NMR (CDCl3): δ(ppm) 2.18 (bs, 6H), 3.64 (s, 3H), 5.40 (dd, 1H, 5 Hz, 7 Hz), 5.66 (d, 1H, 5 Hz), 7.15-8.00 (m, 10H). ##STR78##
Dispersed in 2 ml of methanol were 41.2 mg of methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenate and 46.5 mg of dibenzothiazolyldisulfide. A 0.5 ml quantity of a 5% aqueous solution of hydrochloric acid was added to the dispersion and the mixture was stirred at room temperature for 40 minutes. The same subsequent procedure as in Example 1 was conducted to provide 49.1 mg of methyl 2-(4-(2-benzothiazolyl)dithio-3-phenylacetamide-2-oxo-azetidine-1-yl)-3-methyl-2-butenate in 75% yield. The product thus obtained was found identical in IR and 1 HNMR data with those of the compound produced in Example 1.
Reaction was conducted between methyl 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-3-butenate and dibenzothiazolyldisulfide in solvents with the results as shown in Table 3 below. The reaction conditions other than those indicated in Table 3 were the same as Example 1. The compound (I) obtained was found identical in IR and 1 HNMR data with the compound produced in Example 2.
TABLE 3
__________________________________________________________________________
Compound (II)
Compound (III) Time
(I)
Ex.
mg R.sup.3BT mg
Solvent ml
5% HCl ml
(min)
Yield (%)
__________________________________________________________________________
27 50.3 52.4 DMF (3)
5% HCl 5 55
(0.8)
28 40.7 49.9 MeCN (2)
5% HCl 55 63
(0.5)
29 40.5 46.9 MeOH (2)
5% HCl 40 58
(0.5)
30 41.1 48.1 CH.sub.3 COCH.sub.3
(3)
.sub. 10% HClO.sub.4
40 94
CH.sub.2 Cl.sub.2
(1)
(0.5)
__________________________________________________________________________
Note:
##STR80##
DMF stands for demethylformamide; MeCN, acetonitrile; and MeOH, methanol.
##STR81##
Dissolved in 2 ml of tetrahydrofuran were 41.1 mg of the compound (II) wherein R1 is CH2 Ph and R2 is ##STR82## and 30.7 mg of the compound (III) wherein R3 is ##STR83## To the solution was added 0.5 ml of a 5% aqueous solution of hydrochloric acid and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate. The dilute was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off. The resulting residue was separated and purified by silica gel column chromatography, giving 46.4 mg of a compound (I) wherein R1 is CH2 PH, R2 is ##STR84## and R3 is ##STR85## in 72% yield. The compound (I) thus obtained was found identical in IR and 1 HNMR data with the standard compound (I).
Compounds (I) was prepared from compounds (II) and (III) by following the same procedure as Example 30. Table 4 below shows the results. The compounds (I) thus obtained were identical in IR and 1 HNMR data with the standard compound (I).
TABLE 4
______________________________________
Compound (III)
Ex. Compound (II)R.sup.1 R.sup.2
##STR86## Reac- tion time (Min.)
(%)(I)
______________________________________
32 PhCH.sub.2
##STR87##
##STR88## 30 64
33 PhCH.sub.2
##STR89##
##STR90## 30 51
______________________________________
The procedure of Example 1 was repeated, producing the compounds (I) as shown below in Table 5 which also indicates IR and 1 HNMR data of the compounds (I) thus obtained.
TABLE 5
__________________________________________________________________________
##STR91## (I)
Compound (I)
Ex.
R.sup.1
R.sup.2 R.sup.3 IR and .sup.1 HNMR Data
__________________________________________________________________________
34 PhCH.sub.2
##STR92##
##STR93##
IR (CDCl.sub.3) 3390, 1783, 1723, 1670
cm.sup.-1 NMR (400MHz, CDCl.sub.3,
δ) 3.38 (s, 3H), 3.75 (ABq, 2H,
16.4Hz), 4.24 and 4.84 (ABq, 2H,
12.6Hz), 4.45 and 5.10 (ABq, 2H,
14.0Hz), 4.95 (dd, 1H, 5.3Hz, 7.5Hz),
5.48 (d, 1H, 5.3Hz), 6.36 (d, 1H,
7.5Hz), 7.30 (s, 5H), 7.30-7.95 (m,
5H)
35 PhCH.sub.2
##STR94##
##STR95##
IR (CHCl.sub.3) 3390, 1780, 1723, 1672
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.39 (s, 3H), 3.68 (bs, 2H), 4.09 and
4.89 (ABq, 2H, 15Hz), 4.88 and 5.36
(ABq, 2H, 14Hz), 4.99 (dd, 1H, 5Hz,
8Hz), 5.46 (d, 1H, 5Hz), 6.77 (d, 1H,
8Hz), 7.10-8.10 (m, 19H)
36 PhCH.sub.2
##STR96##
##STR97##
IR (CHCl.sub.3) 3400, 1780, 1724, 1675
cm.sup.-1 NMR (CDCl.sub.3, δ)
1.40 (t, 6H, 7Hz), 3.56 (s, 3H), 3.74
(bs, 2H), 4.34 and 4.54 (ABq, 2H,
13Hz), 4.50 (bs, 2H), 4.67 (q, 4H,
7Hz), 5.13 (dd, 1H, 5Hz, 8Hz), 5.59 (d,
1H, 5Hz), 6.59 (d, 1H, 8Hz), 7.37 (s,
5H), 7.20-8.00 (m, 4H)
37 PhCH.sub.2
##STR98##
##STR99##
IR (CHCl.sub.3) 3390, 1778, 1720, 1672
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.59 (s, 3H), 3.68 (s, 2H), 4.70 and
4.91 (ABq, 2H, 13Hz), 4.83 (bs, 2H),
5.17 (dd, 1H, 5Hz, 8Hz), 5.63 (d, 1H,
5Hz), 6.75 (d, 1H, 8Hz), 7.10-8.00 (m,
17H)
38 PhCH.sub.2
##STR100##
##STR101##
IR (CHCl.sub.3) 3380, 1777, 1717, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.63 (bs, 2H), 4.11 (d, 1H, 15Hz),
4.55-5.14 (m, 5H), 5.32 (d, 1H, 5Hz),
5.38 (d, 1H, 14Hz), 6.57 (d, 1H, 8Hz),
7.10-8.00 (m, 24H)
39 PhCH.sub.2
##STR102##
##STR103##
IR (CHCl.sub.3) 3380, 1778, 1714, 1669
cm.sup.-1 NMR (CDCl.sub.3, δ)
1.38 (t, 6H, 7Hz), 3.66 (bs, 2H), 4.44
and 4.48 (ABq, 2H, 13Hz), 4.50 (bs,
2H), 4.62 (q, 4H, 7Hz), 4.93 (dd, 1H,
5Hz, 8Hz), 4.74 and 5.08 (ABq, 2H,
12Hz), 5.45 (d, 1H, 5Hz), 6.59 (d, 1H,
8Hz), 7.15 (s, 5H), 7.30 (s, 5H),
7.10-7.90 (m, 4H)
40 PhCH.sub.2
##STR104##
##STR105##
IR (CHCl.sub.3) 3390, 1778, 1712, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.56 (bs, 2H), 4.63 and 4.83 (ABq, 2H,
13Hz), 4.68 and 4.86 (ABq, 2H, 14Hz),
4.90 and 5.08 (ABq, 2H, 12Hz), 4.98
(dd, 1H, 5Hz, 8Hz), 5.48 (d, 1H, 5Hz),
6.62 (d, 1H, 8Hz), 7.10 (s, 5H), 7.23
(s, 5H), 7.00- 7.90 (m, 12H)
41 PhCH.sub.2
##STR106##
##STR107##
IR (CHCl.sub.3) 3400, 1780, 1720, 1672
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.73 (bs, 2H), 8.86 (s, 3H), 8.89 (s,
3H), 4.59 and 4.75 (ABq, 2H, 14Hz),
4.63 (bs, 2H), 4.92 (dd, 1H, 5Hz, 8Hz),
.99 and 5.13 (ABq, 2H, 12Hz), 5.48 (d,
1H, 5Hz), 7.17 (s, 5H), 7.32 (s, 5H),
7.20-7.99 (m, 5H)
42 PhCH.sub.2
##STR108##
##STR109##
IR (CHCl.sub.3) 3400, 1777, 1717, 1683
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.70 (bs, 6H), 3.75 (bs, 2H), 4.50 and
4.73 (ABq, 2H, 13Hz), 4.50 and 4.87
(ABq, 2H, 14Hz), 4.98 and 5.13 (ABq,
2H, 12Hz), 5.40-5.60 (m, 2H), 7.10 (s,
5H), 7.10-7.90 (m, 10H)
43 PhCH.sub.2
##STR110##
##STR111##
IR (CHCl.sub.3) 3400, 1780, 1720, 1671
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.57 (s, 3H), 3.72 (s, 2H), 4.62 and
4.78 (ABq, 2H, 10Hz), 4.70 (s, 2H),
4.97 (dd, 1H, 5Hz, 7Hz), 5.58 (d, 1H,
5Hz), 6.63 (d, 1H, 7Hz), 7.33 (s, 5H),
7.20-7.90 (m, 4H)
44 PhCH.sub.2
##STR112##
##STR113##
IR (CHCl.sub.3) 3350, 1775, 1721, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.55 (s, 2H), 3.71 (s, 3H), 4.24 (bs,
2H), 5.18 (s, 1H), 5.20-5.50 (m, 3H),
5.48 (s, 1H), 7.00-7.70 (m, 8H), 8.40
(bd, 2H, 5.5Hz)
45 PhCH.sub.2
##STR114## Ph IR (CHCl.sub.3) 3380, 1770, 1730, 1680
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.51 (s, 2H), 3.68 (s, 3H), 4.10 (bs,
2H), 4.94 (s, 1H), 5.11 (s, 1H),
5.20-5.50 (m, 3H), 6.12 (d, 1H, 8Hz),
7.10-7.60 (m, 10H)
46 PhCH.sub.2
##STR115##
##STR116##
IR (CHCl.sub.3) 3280, 1775, 1720, 1675
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.70 (s, 3H), 3.66 (s, 2H), 3.79 (s,
3H), 4.26 (bs, 2H), 5.05-5.35 (m, 3H),
5.56 (s, 1H), 5.62 (d, 1H, 4.5Hz), 7.00
(d, 1H, 9Hz), 7.32 (s, 5H)
47 PhCH.sub.2
##STR117##
##STR118##
IR (CHCl.sub.3) 3390, 1770, 1735, 1658
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.62 (s, 2H), 3.74 (s, 3H), 4.23 (bs,
2H), 5.14 (dd, 1H, 5Hz, 8Hz), 5.25 (s,
1H), 5.34 (s, 1H), 5.50 (s, 1H), 5.61
(d, 1H, 5Hz), 6.90 (d, 1H, 8Hz), 7.23
(s, 5H), 7.55 (bs, 5H)
48 PhCH.sub.2
##STR119##
##STR120##
IR (CHCl.sub.3) 3390, 1780, 1725, 1660
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.60 (s, 2H), 3.77 (s, 3H), 3.97 (s,
3H), 4.24 (bs, 2H), 5.10 (dd, 1H, 5Hz,
8Hz), 5.21 (s, 2H), 5.47 (s, 1H), 5.66
(d, 1H, 5Hz), 7.04 (d, 1H, 8Hz), 7.26
(s, 5H)
49 PhCH.sub.2
##STR121##
##STR122##
IR (CHCl.sub.3) 3390, 1785, 1730, 1670
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.70 (s, 2H), 3.80 (s, 3H), 4.27 (bs,
2H), 5.17 (s, 1H), 5.25-5.45 (m, 3H),
5.61 (s, 1H), 6.72 (bd, 1H, 8Hz), 7.37
(s, 5H), 7.51 (d, 2H, 9Hz), 8.12 (d,
2H, 9Hz)
50 PhCH.sub.2
##STR123##
##STR124##
IR (CHCl.sub.3) 3280, 1775, 1740, 1665
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.69 (s, 3H), 4.16 and 4.40 (ABq, 2H,
12Hz), 5.21 (dd, 1H, 5Hz, 8Hz), 5.30
(bs, 2H), 5.53 (d, 1H, 5Hz), 5.56 (s,
1H), 7.02 (d, 1H, 8Hz), 7.20-7.60 (m,
7H), 7.55-7.95 (m, 2H)
51 PhCH.sub.2
##STR125##
##STR126##
IR (CHCl.sub.3) 3380, 1780, 1735, 1680
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.65 (s, 2H), 4.22 (bs, 2H), 5.20 (s,
2H), 5.05-5.40 (m, 4H), 5.53 (s, 1H),
6.81 (bd, 1H, 8Hz), 7.34 (s, 10H), 7.42
(d, 2H, 9Hz), 8.05 (d, 2H, 9Hz)
52 PhCH.sub.2
##STR127##
##STR128##
IR (neat) 3280, 1775, 1740, 1665
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.62 (s, 3H), 3.60 (s, 2H), 4.21 (bs,
2H), 5.05-5.40 (m, 3H), 5.16 (s, 2H),
5.46 (s, 1H), 5.55 (d, 1H, 4.5Hz),
7.10-7.45 (m, 11H)
53 PhCH.sub.2
##STR129##
##STR130##
IR (neat) 3260, 1770, 1735, 1655
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.55 (s, 2H), 4.24 (bs, 2H), 4.96 (s,
1H), 5.05-5.40 (m, 3H), 5.27 (s, 2H),
5.68 (d, 1H, 5Hz), 6.16 (d, 1H, 8Hz),
7.15-7.45 (m, 10H)
54 PhOCH.sub.2
##STR131##
##STR132##
IR (neat) 3310, 1780, 1745, 1685
cm.sup.-1 NMR (CDCl.sub.3, δ)
2.63 (s, 3H), 4.27 (bs, 2H), 4.58 (s,
2H), 5.24 (s, 2H), 5.20-5.60 (m, 4H),
5.70 (d, 1H, 5Hz), 6.70-7.60 (m, 11H)
55 PhOCH.sub.2
##STR133##
##STR134##
IR (neat) 3300, 1775, 1740, 1680
cm.sup.-1 NMR (CDCl.sub.3, δ)
4.17 (bs, 2H), 4.38 (bs, 2H), 5.02 (s,
1H), 5.20 (s, 2H), 5.20-5.50 (m, 3H),
5.80 (d, 1H, 5Hz), 6.70-7.50 (m, 11H)
56 PhCH.sub.2
##STR135##
##STR136##
IR (neat) 3160, 1770, 1735, 1650
cm.sup.-1 NMR (CDCl.sub.3, δ)
3.63 (s, 2H), 4.10 (s, 2H), 5.18 (s,
2H), 5.10-5.60 (m, 5H), 7.00-7.70 (m,
15H), 8.03 (bd, 1H, 6Hz)
57 PhCH.sub.2
##STR137##
##STR138##
IR (CHCl.sub.3) 3280, 1780, 1740, 1670,
640, 1270 cm.sup.- 1 NMR (CDCl.sub.3,
δ) 3.66 (s, 2H), 5.10 (s, 2H),
5.14 (s, 2H), 5.00-5.30 (m, 2H), 5.40
(s, 1H), 5.51 (d, 1H, 5Hz), 5.56 (s,
1H), 6.56 (d, 1H, 7.5Hz), 7.10-7.60 (m,
12H), 7.68-8.00 (m, 2H)
__________________________________________________________________________
Dispersed in 3 ml of tetrahydrofuran were 60 mg of benzyl 2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-3-butenate and 62 mg of 5,5'-dimethoxybenzothiazolyldisulfide. To the solution was added 0.75 ml of a 5% aqueous solution of hydrochloric acid and the mixture was stirred at room temperature for 40 minutes.
To the reaction mixture was added 10 ml of ethyl acetate and the insolubles were removed by a glass filter. The filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off.
The resulting residue was separated and purified by silica gel column chromatography, giving 78.5 mg of benzyl 2-(4-(5-methoxybenzothiazole-2-yl)dithio-3-phenylacetamide-2-oxo-azetidine-1-yl)-3-methyl-2-butenate in 87% yield.
NMR (CDCl3): δ(ppm): 1.94 (s, 3H), 3.81 (s, 3H), 4.48 and 4.55 (ABq, 2H, J=1.25 Hz), 4.98 (s, 1H), 5.02 (s, 1H), 5.17 (s, 3H), 5.20-5.70 (m, 2H), 6.70-7.60 (m, 14H).
The procedure of Example 58 was followed to give the compounds (I) as shown in Table 6 below, which also indicates the yields and 1 HNMR data of the compound (I) thus obtained.
TABLE 6
__________________________________________________________________________
##STR140##
Ex. R.sup.1
R R.sup.3 NMR (CDCl.sub.3, δ,
Yield
__________________________________________________________________________
59 PhOCH.sub.2
##STR141##
##STR142## 1.98 (s, 3H), 4.59 (s, 2H), 5.01
(s, 1H), 5.04 (s, 1H), 5.19 (s,
2H), 5.22 (s, 1H), 5.45 (dd, 1H,
J=4.8 and 8.1Hz), 5.65 (d, 1H,
J=4.8Hz), 6.80-7.50 (m, 11H),
7.85 (d, 1H, J=9.0Hz), 8.26 (dd,
1H, J=2.3 and 9.0Hz), 8.54 (d,
1H, J=2.3Hz) 89%
60 PhOCH.sub.2
##STR143##
##STR144## 2.03 (s, 2H), 2.40 (s, 3H), 4.46
and 4.53 (ABq, 2H, J=12.5Hz),
5.18 (s, 1H), 5.15-5.70 (m, 6H),
6.75-7.85 (m, 13H) 89%
61 PhOCH.sub.2
##STR145##
##STR146## 1.95 (s, 3H), 2.67 (s, 3H), 2.87
(s, 6H), 3.94 (s, 2H), 4.46 and
4.53 (ABq, 2H, J=12Hz), 4.95 (s,
1H), 5.10 (s, 1H), 5.15 (s, 1H),
5.30-5.70 (m, 4H), 6.70-7.60 (m,
9H) 88%
62 PhOCH.sub.2
##STR147##
##STR148## 1.94 (s, 3H), 3.82 (s, 9H), 4.51
(bs, 2H), 4.44 (s, 1H), 5.01 (s,
1H), 5.06 (s, 2H), 5.14 (s, 1H),
5.30-5.65 (m, 2H), 6.50 (s, 2H),
6.75-7.85 (m, 10H) 82%
63 PhOCH.sub.2
##STR149##
##STR150## 1.93 (s, 3H), 3.75 (s, 3H), 4.50
(bs, 2H), 4.93 (s, 1H), 4.96 (s,
1H), 5.08 (s, 2H), 5.13 (bs, 1H),
5.42 (dd, 1H, J=4.0 and 6.5Hz),
5.56 (d, 1H, J=4Hz), 6.65-7.90
(m, 14H) 91%
64 PhOCH.sub.2
##STR151##
##STR152## 1.96 (s, 3H), 4.58 and 4.52 (ABq,
H, J=12.5Hz), 5.04 (s, 1H), 5.20
(bs, 2H), 5.52 (dd, 1H, J=4.8 and
8.3Hz), 5.63 (d, 1H, J=4.8Hz),
6.79 (s, 1H), 6.80-7.90 (m,
83%)
65 PhOCH.sub.2
CH.sub.2 OCH.sub.3
##STR153## 1.97 (s, 3H), 3.94 (s, 3H),
4.49-4.54 (ABq, 2H, J=12Hz),
4.75-5.25 (m, 5H), 5.45 (dd, 1H,
J=4.0 and 6.5Hz), 5.58 (d, 1H,
J=4.0Hz), 6.75-7.90 (m,
45%)
66 PhOCH.sub.2
##STR154##
##STR155## 1.97 (s, 3H), 3.85 (s, 3H),
2.35-3.60 (m, 2H), 3.60-3.85 (m,
2H), 4.54 (s, 2H), 4.75-5.75 (m,
7H), 6.75-7.90 (m,
53%)
67 PhCH.sub.2
##STR156##
##STR157## 1.89 (s, 3H), 3.67 (s, 2H), 3.74
(s, 3H), 4.87 (s, 1H), 4.94 (s,
1H), 5.05 (s, 2H), 5.09 (bs, 1H),
5.25 (dd, 1H, J=4.0 and 7.0Hz),
5.45 (d, 1H, J=4.0Hz), 6.45 (d,
1H, J=7.0Hz), 6.55-7.90 (m,
88%)
68 PhCH.sub.2
##STR158##
##STR159## 1.92 (s, 3H), 3.67 (s, 2H), 4.98
(s, 1H), 5.16 (bs, 2H), 5.35 (dd,
1H, J=4.7 and 8.1Hz), 5.52 (d,
1H, J=4.7Hz), 6.31 (d, 1H,
J=8.1Hz), 6.75 (s, 1H), 7.1-7.9
(m, 18H) 82%
69 PhCH.sub.2
##STR160##
##STR161## 1.91 (s, 3H), 2.65 (s, 2H), 3.66
(s, 2H), 3.75 (s, 3H), 4.90 (s,
1H), 4.96 (s, 1H), 5.07 (s, 2H),
5.13 (bs, 1H), 5.28 (dd, 1H,
J=4.8 and 3.1Hz), 5.52 (d, 1H,
J=4.8Hz), 6.10 (d, 1H, J=8.1Hz),
6.80 (d, 2H, J=8.8Hz), 7.00-7.70
(m, 10H) 90%
70 PhCH.sub.2
##STR162##
##STR163## 1.91 (s, 3H), 3.66 (s, 2H), 4.90
(s, 1H), 4.96 (s, 1H), 5.16 (s,
2H), 5.26 (dd, 1H, J=4.0 and
9.0Hz), 5.39 (d, 1H, J=4.0Hz),
6.18 (d, 1H, J=9.0Hz), 7.20-7.90
(m, 11H), 8.10 (d, 2H,
89%.0Hz)
71 PhCH.sub.2
##STR164##
##STR165## 1.95 (s, 2H), 3.69 (s, 2H), 4.94
(s, 1H), 5.02 (s, 1H), 5.15 (s,
1H), 5.20-5.60 (m, 4H), 6.31 (d,
1H, J=9.0Hz), 7.30-8.10 (m,
88%)
72 PhOCH.sub.2
##STR166##
##STR167## 2.00 (s, 3H), 2.32 (s, 3H), 3.28
(bs, 2H), 4.53 (bs, 2H), 5.09
(bs, 1H), 5.24 (bs,
2H), 5.40-5.60 (m, 2H), 6.75-8.00
(m, 10H) 79%
73 PhOCH.sub.2
PhCH.sub.2
##STR168## 1.96 (s, 3H), 4.56 (s, 2H), 4.95
(s, 1H), 4.98 (s, 1H), 5.16 (s,
2H), 5.42 (dd, 1H, J=4.0 and
7.0Hz), 5.59 (d, 1H, J=4.0Hz),
6.65-7.35 (m, 11H), 7.49 (d, 1H,
J=8.0Hz), 7.71 (d, 1H, J=8.0Hz),
8.05 (s, 1H) 85%
74 PhOCH.sub.2
PhCH.sub.2
##STR169## 1.94 (s, 3H), 2.63 (s, 3H), 4.46
and 4.53 (ABq, 2H, J=13Hz), 4.93
(s, 1H), 4.96 (s, 1H), 5.19 (s,
3H), 5.43 (dd, 1H, J=4.0 and
8.0Hz), 5.57 (d, 1H, J=4.0Hz),
6.75-7.50 (m, 14H) 86%
__________________________________________________________________________
Dimethylformamide (0.5 ml) was added to 30 mg of benzyl 2-(3-phenylacetamide-4-((1-methyltetrazole-5-yl)thio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenate to obtain a uniform solution. The solution was cooled to -25° C. Thereto was added 40 ml of a about 2M solution of ammonia gas dissolved in dimethylformamide and the mixture was stirred for 1 hour. Four drops of 5% aqueous solution of hydrochloric acid were added and the mixture was vigorously agitated to warm to room temperature. The resulting mixture was diluted with 5 ml of ethyl acetate. The dilute was washed with a saturated aqueous solution of sodium chloride, dried over Na2 SO4 and concentrated. The residue thus obtained was subjected to silica gel column chromatography using a 15:1 benzeneethyl acetate mixture, giving 20.8 mg of benzyl 7-phenylacetamide-3-((1-methyltetrazole-5-yl)thiomethyl)-3-cephem-4-carboxylate.
The compound thus prepared was chemically analyzed with the following result.
IR (nujol): 3265, 1780, 1710, 1655 cm-1.
NMR (CDCl3): δ(ppm) 3.63 (s, 2H), 3.70 (s, 2H), 3.90 (s, 3H), 4.24 and 4.53 (ABq, 2H, 14 Hz), 4.95 (d, 1H, 5 Hz), 5.31 (s, 2H), 5.85 (dd, 1H, 5 Hz, 9 Hz), 6.21 (d, 1H, 9 Hz), 7.32 (s, 5H), 7.40 (s, 5H).
Claims (9)
1. A process for preparing an azetidinone compound represented by the formula ##STR171## wherein R1 represents a straight-chain or branched-chain lower alkyl group, phenyl, p-nitrophenyl, p-chlorophenyl, benzyl, p-nitrophenylmethyl, p-chlorophenylmethyl, p-methoxyphenylmethyl, diphenylmethyl, phenoxymethyl, p-nitrophenoxymethyl or p-chlorophenoxymethyl, R2 represents hydrogen, acetyl, propionyl, butyryl, trimethylsilyl, dimethylbutylsilyl, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, diphenylphosphonyl, dibenzylphosphonyl, diethylphosphonyl, or a group represented by the formula ##STR172## wherein R is hydrogen or a carboxyl-protecting group, Z1 and Z2 are the same or different and are each hydrogen, a halogen, methylthio, ethylthio, phenylthio, p-nitrophenylthio, pentachlorophenylthio, 2-pyridylthio, 2-benzothiadiazolylthio, 1,3,4-thiadiazole-5-ylthio, 2-substituted-1,3,4-thiadiazole-5 -ylthio, 1,2,3,4-tetrazole-5-ylthio, 1-substituted-1,2,3,4-tetrazole-5-ylthio, ethoxythiocarbonylthio, N,N-diethyldithiocarbamate, N,N-dimethyldithiocarbamate, phenylsulfonyl, p-methylphenylsulfonyl, hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, nitrosoxy, nitryloxy, dimethylamino or piperidine-1-yl, and W is a protected hydroxyl group, and R3 represents phenyl, p-nitrophenyl, pentachlorophenyl or a group formed by eliminating one hydrogen atom from an aromatic heterocyclic compound containing a single heterocyclic ring (optionally fused to a benzene ring) of 5-6 members with no more than 4 heteroatoms selected from the group consisting of nitrogen and sulfur, said aromatic heterocyclic compound optionally having methyl, nitro, methoxy, --CF3 or phenyl as a substituent, said process comprising reacting a thiazolinoazetidinone compound represented by the formula ##STR173## wherein R1 and R2 are as defined above with a sulphur-containing compound represented by the formula
R.sup.3 --S--Y (III)
wherein R3 is as defined above and Y represents --SR3 (in which R3 is as defined above), diethylamino, diisopropylamino, cyclohexylamino, morpholino, piperidino, pyrrolidino, phthalimido or succinimido in the presence of an acid in a hydrous organic solvent.
2. A process as defined in claim 1 in which the compound (III) is used in an amount of about 1 to about 10 moles per mole of the compound of the formula (II).
3. A process as defined in claim 1 or 2 in which the acid is a mineral acid, sulfonic acid, α-halocarboxylic acid or polycarboxylic acid.
4. A process as defined in claim 1 or 2 in which the acid is a member selected from the class consisting of perchloric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, hydrofluoric acid, nitric acid, phosphoric acid, benzenesulfonic acid and toluenesulfonic acid.
5. A process as defined in any one of claims 1 or 2 in which the compound of the formual (II) is one wherein R1 is benzyl, phenoxymethyl, p-chlorophenoxymethyl or phenyl.
6. A process as defined in any one of claims 1 to 5 in which the compound of formula (II) is one wherein R2 is hydrogen, ##STR174## (in which R is hydrogen or a carboxyl-protecting group, and Z1 and Z2 are the same or different and are each hydrogen, halogen, methylthio, ethylthio, phenylthio, p-nitrophenylthio, pentachlorophenylthio, 2-pyridylthio, 2-benzothiadiazolylthio, 1,3,4-thiadiazole-5-ylthio, 2-methyl-1,3,4-thiadiazole-6-ylthio, 1,2,3,4-tetrazole-5-ylthio, 1-phenyl-1,2,3,4-tetrazole-5-ylthio, 1-methyl-1,2,3,4-tetrazole-5-ylthio, ethoxythiocarbonylthio, N,N-diethyldithiocarbamate, N,N-dimethyldithiocarbamate, phenylsulfonyl, p-methylphenylsulfonyl, hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, nitrosoxy, nitryloxy, dimethylamino or piperidine-1-yl).
7. A process as defined in claim 1 in which the compound of formula (III) is one wherein Y is --SR3 (in which R3 is benzothiazolyl-1-yl, 5-methyl-1,3,4-thiazolyl-2-yl, 5-phenyl-1,3,4-thiazolyl-2-yl or benzoimidazolyl-2-yl).
8. A process as defined in claim 1 wherein R3 is phenyl, p-nitrophenyl, pentachlorophenyl, or a group formed by eliminating one hydrogen atom from an aromatic heterocyclic compound selected from the group consisting of pyridine, benzimidazole, benzothiazole, tetrazole and thiadiazole, said aromatic heterocyclic compound being optionally substituted with methyl, methoxy, nitro, phenyl or trifluoromethyl.
9. A process as defined in claim 1 wherein R3 is phenyl, p-nitrophenyl, pentachlorophenyl, 2-benzothiazolyl, 5-methoxybenzothiazole-2-yl, 5-nitro-benzothioazole-2-yl, 5-methylbenzothiazole-2-yl, 5-trifluoromethyl-benzothiazole-2-yl, 7-methyl-benzothiazole-2-yl, 2-benzoimidazolyl, 2-pyridyl, 1,2,3,4-tetrazole-5-yl, 1-phenyl-1,2,3,4-tetrazole-5-yl, 1-methyl-1,2,3,4-tetrazole-5-yl, 2-methyl-1,3,4-thiadiazole-5-yl or 2-phenyl-1,3,4-thiadiazole-5-yl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57-155674 | 1982-09-06 | ||
| JP57155674A JPS5944356A (en) | 1982-09-06 | 1982-09-06 | Preparation of azetidinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4622178A true US4622178A (en) | 1986-11-11 |
Family
ID=15611095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/608,695 Expired - Lifetime US4622178A (en) | 1982-09-06 | 1983-09-06 | Process for preparing azetidinone derivatives |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4622178A (en) |
| EP (1) | EP0117875B1 (en) |
| JP (1) | JPS5944356A (en) |
| DE (1) | DE3372613D1 (en) |
| WO (1) | WO1984000960A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5955888A (en) | 1982-09-24 | 1984-03-31 | Otsuka Chem Co Ltd | Azetidinone compound |
| US5986091A (en) * | 1996-03-13 | 1999-11-16 | Otsuka Kagaku Kabushiki Kaisha | Process for preparation of β-lactam compounds |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1410371A (en) * | 1972-01-28 | 1975-10-15 | Glaxo Lab Ltd | Substituted azetidinones |
-
1982
- 1982-09-06 JP JP57155674A patent/JPS5944356A/en active Granted
-
1983
- 1983-09-06 US US06/608,695 patent/US4622178A/en not_active Expired - Lifetime
- 1983-09-06 EP EP83902900A patent/EP0117875B1/en not_active Expired
- 1983-09-06 WO PCT/JP1983/000298 patent/WO1984000960A1/en not_active Ceased
- 1983-09-06 DE DE8383902900T patent/DE3372613D1/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1410371A (en) * | 1972-01-28 | 1975-10-15 | Glaxo Lab Ltd | Substituted azetidinones |
Non-Patent Citations (3)
| Title |
|---|
| Bennett, "Concise Chemical & Technical Dictionary", 3rd Edition 1974, p. 559. |
| Bennett, Concise Chemical & Technical Dictionary , 3rd Edition 1974, p. 559. * |
| Micetich et al, Can J. Chem 59, 1020 (1981). * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0117875B1 (en) | 1987-07-22 |
| WO1984000960A1 (en) | 1984-03-15 |
| EP0117875A1 (en) | 1984-09-12 |
| EP0117875A4 (en) | 1984-07-24 |
| JPS5944356A (en) | 1984-03-12 |
| DE3372613D1 (en) | 1987-08-27 |
| JPH0136824B2 (en) | 1989-08-02 |
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